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TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor.
The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2- [(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:
 |
Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20 °C.
TYBOST tablets are for oral administration. Each tablet contains 150 mg of cobicistat. The tablets include the following inactive ingredients: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, sunset yellow FCF (FD&C Yellow #6) aluminum lake, and iron oxide yellow.
The following adverse reaction is described in greater detail in another section of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of TYBOST is based on Week 144 data from a Phase 3 trial, Trial 114, in which 692 HIV-1 infected, antiretroviral treatment-naïve subjects received:
The most common adverse reactions (Grades 2−4) and reported in >5% of subjects in the TYBOST group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 11% in both the TYBOST and ritonavir groups. Table 3 displays the frequency of adverse reactions (Grades 2−4) occurring in at least 2% of subjects in the TYBOST group in Trial 114.
Table 3 Selected Adverse Reactionsa (Grades 2−4) Reported in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)
| TYBOST Coadministered with Atazanavir + TRUVADA N=344 |
Ritonavir Coadministered with Atazanavir + TRUVADA N=348 |
|
| Jaundice | 6% | 3% |
| Rashb | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
| a. Frequencies of adverse reactions are based on Grades 2−4 adverse events attributed to study drugs. b.Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, and urticaria. |
||
Selected adverse reactions of at least moderate severity (≥Grade 2) occurring in less than 2% of subjects receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir.
Gastrointestinal Disorders: vomiting, upper abdominal pain
General Disorders and Administration Site Conditions: fatigue
Musculoskeletal and Connective Tissue Disorders:habdomyolysis
Psychiatric Disorders: depression, abnormal dreams, insomnia
Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis
Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.
The frequency of laboratory abnormalities (Grades 3−4) occurring in at least 2% of subjects in the TYBOST group in Trial 114 is presented in Table 4.
Table 4 Laboratory Abnormalities (Grades 3−4) in ≥2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Trial 114 (Week 144 Analysis)
| TYBOST + Atazanavir + TRUVADA | Ritonavir + Atazanavir + TRUVADA | |
| Laboratory Parameter Abnormality | N=344 | N=348 |
| Total Bilirubin (>2.5 x ULN) | 73% | 66% |
| Creatine Kinase (≥10.0 x ULN) | 8% | 9% |
| Urine RBC (Hematuria) (>75 RBC/HPF) | 6% | 3% |
| ALT (>5.0 x ULN) | 6% | 3% |
| AST (>5.0 x ULN) | 4% | 3% |
| GGT (>5.0 x ULN) | 4% | 2% |
| Serum Amylasea (>2.0 x ULN) | 4% | 2% |
| Urine Glucose (Glycosuria) (≥1000 mg/dL) | 3% | 3% |
| Neutrophils (<750/mm3) | 3% | 2% |
| Serum Glucose (Hyperglycemia) (>250 mg/dL) | 2% | 2% |
| a. For subjects with serum amylase >1.5 x upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3−4) occurring in the TYBOST (N=46) and ritonavir (N=35) groups was 7% and 3%, respectively. | ||
TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. In Trial 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was –15.1 ± 16.5 mL/min in the TYBOST group and –8.0 ± 16.8 mL/min in the ritonavir group.
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.
Table 5 Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Trial 114 (Week 144 Analysis)
| TYBOST + Atazanavir + TRUVADA | Ritonavir + Atazanavir + TRUVADA | |||
| Baseline | Week 144 | Baseline | Week 144 | |
| mg/dL | Change from baselinea | mg/dL | Change from baselinea | |
| Total Cholesterol (fasted) | 163 [N=219] | +11 [N=219] | 165 [N=227] | +13 [N=227] |
| HDL-cholesterol (fasted) | 43 [N=218] | +7 [N=218] | 43 [N=228] | +6 [N=228] |
| LDL-cholesterol (fasted) | 102 [N=218] | +11 [N=218] | 104 [N=228] | +16 [N=228] |
| Triglycerides (fasted) | 130 [N=219] | +14 [N=219] | 131 [N=227] | +14 [N=227] |
| a. The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. Analysis excludes subjects receiving an HMG-CoA reductase inhibitor drug. | ||||
The safety of TYBOST was evaluated in HIV-1 infected virologically suppressed pediatric subjects between the ages of 12 to less than 18 years through Week 48 in an open-label clinical trial (Trial 128) of TYBOST coadministered with atazanavir (N=14) or darunavir (N=7) plus two nucleoside reverse transcriptase inhibitors [see Clinical Studies]. In this trial, the safety profile of TYBOST was similar to that in adults.
Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp), BCRP, OATP1B1, and OATP1B3. The plasma concentration of drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1, or OATP1B3 may be increased if those drugs are coadministered with TYBOST.
Based on in vitro data, cobicistat is not expected to induce CYP1A2 or CYP2B6 and based on in vivo data, cobicistat is not expected to induce MDR1 or, in general, CYP3A to a clinically significant extent. The induction effect of cobicistat on CYP2C9, CYP2C19, or UGT1A1 is unknown, but is expected to be low based on CYP3A in vitro induction data.
Coadministration of TYBOST with atazanavir or darunavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s). Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.
Cobicistat is metabolized by CYP3A, and to a minor extent, by CYP2D6. Atazanavir and darunavir are also metabolized by CYP3A.
Coadministration of TYBOST with atazanavir or darunavir in combination with drugs that induce CYP3A activity have the potential to decrease plasma concentrations of cobicistat, atazanavir, and darunavir, which may lead to loss of therapeutic effect and development of resistance (see Table 6).
Coadministration of TYBOST with atazanavir or darunavir in combination with other drugs that inhibit CYP3A may further increase the plasma concentrations of cobicistat, atazanavir, and darunavir (see Table 6).
Coadministration of TYBOST with fosamprenavir, saquinavir, or tipranavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Use of TYBOST with lopinavir is not recommended because lopinavir is co-formulated with ritonavir.
Table 6 provides dosing recommendations as a result of drug interactions with TYBOST coadministered with atazanavir or darunavir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of the interaction and potential for serious adverse events or loss of therapeutic effect [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
In Table 6, if not specifically stated, the drug interaction information applies to both coadministered agents: TYBOST coadministered with atazanavir or darunavir [see CLINICAL PHARMACOLOGY].
In addition to the drug interactions noted in Table 6, TYBOST is not recommended for use in combination with fixed-dose combination tablets that contain cobicistat, lopinavir/ritonavir or regimens containing ritonavir, or in combination with more than one antiretroviral agent that requires pharmacokinetic enhancement [see WARNINGS AND PRECAUTIONS].
Evaluate whether dosing adjustments of concomitant medications or coadministered antiretroviral drugs are necessary in:
Under these circumstances, also monitor for adverse events and/or monitor concentrations of concomitant medications if appropriate.
No dose adjustment is required when TDF or rilpivirine are coadministered with TYBOST and atazanavir or darunavir.
Table 6 Established and Other Potentially Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
| Concomitant DrugClass: Drug Name |
Potential Effectb | Clinical Comment |
| Antiretroviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| efavirenz | ↓ cobicistat ↓ darunavir ↓ atazanavir |
TYBOST coadministered with darunavir: Coadministration of darunavir and TYBOST withefavirenz is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir. TYBOST coadministered with atazanavir: In treatment-naïve patients: Atazanavir 400 mg with TYBOST 150 mg should be coadministered once daily as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Coadministration of atazanavir and TYBOST with efavirenz in treatment-experienced patients is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir. |
| etravirine | ↓ cobicistat darunavir: effect unknown ↓ atazanavir |
Coadministration with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir ordarunavir. |
| nevirapine | ↓ atazanavir ↑nevirapine |
Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions. |
| ↓ cobicistat darunavir: effect unknown | TYBOST coadministered with darunavir: TYBOST coadministration with nevirapine and darunavir is not recommended because it may result in the loss of therapeutic effect and development of resistance to darunavir. |
|
| Antiretroviral Agents: CCR5 Antagonists | ||
| maraviroc | ↑ maraviroc | Maraviroc is a substrate of CYP3A. When coadministering with maraviroc, patients should receive maraviroc 150 mg twice daily. |
| Antiretroviral Agents: Protease Inhibitors | ||
| indinavir | Contraindicated with TYBOST coadministered with atazanavir only: Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. | |
| Other Agents: | ||
| Alpha 1- adrenoreceptor antagonist: alfuzosin |
↑ alfuzosin | Coadministration with alfuzosin is contraindicated due to potential for serious and/or life-threatening reactions such as hypotension. |
| Antianginal ranolazine |
↑ ranolazine | Coadministration with ranolazine is contraindicated due to potential for serious and/or life-threatening reactions. |
| Antacids: e.g., aluminum and magnesium hydroxide (please also see H2 Receptor Antagonists and Proton Pump Inhibitors below) |
↓ atazanavir | TYBOST coadministered with atazanavir: With concomitant use, administer a minimum of 2 hours apart. |
| Antiarrhythmics: dronedarone |
↑ dronedarone | Coadministration with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| digoxin | ↑ digoxin | When coadministering with digoxin, titrate the digoxin dose and monitor digoxin concentrations. |
| Other antiarrhythmics: e.g., amiodarone disopyramide flecainide mexiletine propafenone quinidine |
↑ antiarrhythmics | Clinical monitoring is recommended upon coadministration with antiarrhythmics. |
| Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin |
↑ clarithromycin ↑ erythromycin ↑ telithromycin ↑ cobicistat ↑ atazanavir ↑ darunavir |
Consider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir. |
| Anticancer Agents: irinotecan |
↑ irinotecan | Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with irinotecan is contraindicated due to potential for increased irinotecan toxicity. |
| dasatinib nilotinib vinblastine vincristine |
↑ anticancer agents | A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with TYBOST coadministered with atazanavir or darunavir. Consult the dasatinib and nilotinib prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects. |
| Anticoagulants: Direct Oral Anticoagulants (DOACs) apixaban rivaroxaban betrixaban dabigatran edoxaban |
↑ apixaban | TYBOST coadministered with atazanavir or darunavir: Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with TYBOST depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A and P-gp inhibitors in apixaban prescribing information. |
| ↑ rivaroxaban | Coadministration of rivaroxaban with TYBOST is not recommended because it may lead to an increased bleeding risk. | |
| atazanavir: ↑ betrixaban ↑ dabigatran ↑ edoxaban |
TYBOST coadministered with atazanavir: Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as TYBOST coadministered with atazanavir depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. | |
| darunavir: ↔ betrixaban ↔ dabigatran ↔ edoxaban |
TYBOST coadministered with darunavir: No dose adjustment. |
|
| warfarin | warfarin: effect unknown | Monitor the international normalized ratio (INR) upon coadministration of TYBOST with warfarin. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ atazanavir ↓ darunavir ↓ cobicistat |
Coadministration with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| Anticonvulsants with CYP3A induction effects that are NOT contraindicated e.g., eslicarbazepine, oxcarbazepine |
↓ cobicistat ↓ atazanavir darunavir: effect unknown |
Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response. |
| Anticonvulsants that are metabolized by CYP3A e.g., clonazepam |
↑ clonazepam | Clinical monitoring of anticonvulsants is recommended. |
| Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine |
SSRIs: effects unknown ↑ TCAs ↑ trazodone |
When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, including using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. |
| Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline |
||
| Other antidepressants: trazodone |
||
| Antifungals: itraconazole ketoconazole |
↑ itraconazole ↑ ketoconazole |
Specific dosing recommendations are not available for coadministration with itraconazole or ketoconazole. |
| voriconazole | Voriconazole: effects unknown ↑ cobicistat ↑ atazanavir ↑ darunavir |
Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole. |
| Anti-gout: colchicine |
↑ colchicine | Coadministration with colchicine is contraindicated in patients with renal and/or hepatic impairment due to potential for serious and/or life-threatening reactions. Treatment of gout flares – coadministration of colchicine: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout flares – coadministration of colchicine: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifampin |
↓ atazanavir ↓ darunavir ↓ cobicistat |
Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| rifabutin | ↑ rifabutin cobicistat: effects unknown darunavir: effects unknown atazanavir: effects unknown |
The recommended dosage regimen for rifabutin is 150 mg every other day. Monitor for rifabutin associated adverse reactions including neutropenia and uveitis. |
| Antiplatelets: | ||
| ticagrelor | ↑ ticagrelor | Coadministration with ticagrelor is not recommended. |
| clopidogrel | ↓ clopidogrel active metabolite | Coadministration with clopidogrel is not recommended due to potential reduction of the antiplatelet activity of clopidogrel. |
| prasugrel | ↔ prasugrel active metabolite | No dose adjustment is needed when prasugrel is co-administered with TYBOST. |
| Antipsychotics: | ||
| lurasidone | ↑ lurasidone | Coadministration with lurasidone is contraindicated due to potential for serious and/or life-threatening reactions. |
| pimozide | ↑ pimozide | Coadministration with pimozide is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| quetiapine | ↑ quetiapine | Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking TYBOST coadministered with atazanavir or darunavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Other antipsychotics: e.g., perphenazine risperidone thioridazine |
↑ antipsychotic | A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed upon coadministration. |
| Beta-Blockers: e.g., metoprolol carvedilol timolol |
↑ beta-blockers | Clinical monitoring is recommended for coadministration with beta-blockers that are metabolized by CYP2D6. |
| Calcium Channel Blockers: e.g., amlodipine diltiazem felodipine nifedipine verapamil |
↑ calcium channel blockers | Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. |
| Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone |
↓ cobicistat ↓ atazanavir ↓ darunavir ↑ corticosteroids |
Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir or darunavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.Alternative corticosteroids including beclomethasone,prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan ↓ cobicistat ↓ darunavir ↓ atazanavir |
Initiation of bosentan in patients taking TYBOST coadministered with atazanavir or darunavir: In patients who have been receiving TYBOST coadministered with atazanavir or darunavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of TYBOST coadministered with atazanavir or darunavir. After at least 10 days following the initiation of TYBOST combined with atazanavir or darunavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Switching from ritonavir to TYBOST coadministered with atazanavir or darunavir: Maintain bosentan dose. |
| Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine |
↑ ergot derivatives | Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| H2-Receptor Antagonists: e.g., famotidine |
↓ atazanavir | TYBOST coadministered with atazanavir: Administer atazanavir/TYBOST either at the same time or a minimum of 10 hours after administering H2 receptor antagonists. The dose of the H2-receptor antagonist should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naïve patients or 20 mg twice daily in treatment-experienced patients. TYBOST coadministered with atazanavir and TDF: Treatment-experienced patients: The recommended once daily dosage regimen is TYBOST 150 mg coadministered with atazanavir 400 mg with concomitant use of H2-receptor antagonists and tenofovir. |
| HCV Protease Inhibitors: boceprevir simeprevir |
darunavir: effects unknown atazanavir: effects unknown boceprevir: effects unknown ↑ simeprevir |
No drug interaction data are available. Coadministration with boceprevir or simeprevir is not recommended. |
| Herbal Products: St. John’s wort (Hypericum perforatum) |
↓ atazanavir ↓ darunavir ↓ cobicistat |
Coadministration is contraindicated due to potential for loss of therapeutic effect and development of resistance. |
| Hormonal Contraceptives: | Additional or alternative non-hormonal forms of contraception should be considered when estrogen based contraceptives are coadministered with TYBOST and atazanavir or darunavir. | |
| drospirenone/ethinyl estradiol | atazanavir: ↑ drospirenone |
Contraindicated with TYBOST coadministered with atazanavir only: Coadministration of atazanavir with drospirenone is contraindicated due to potential for drospirenone-associated hyperkalemia. |
| darunavir: ↑ drospirenone ↓ ethinyl estradiol |
TYBOST coadministered with darunavir: For coadministration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. |
|
| Other progestin/estrogen contraceptives | progestin: effects unknown estrogen: effects unknown |
No data are available to make recommendations on the coadministration of TYBOST and atazanavir or darunavir with other hormonal contraceptives. |
| Immuno suppressants: cyclosporine everolimus sirolimus tacrolimus |
↑ immuno-suppressants | These immunosuppressant agents are metabolized by CYP3A. Therapeutic drug monitoring is recommended if coadministered. |
| Inhaled Beta Agonist: salmeterol |
↑ salmeterol | Coadministration with salmeterol is not recommended and may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Lipid-modifying Agents: | ↑ lovastatin ↑ simvastatin |
Coadministration with lovastatin or simvastatin is contraindicated due to potential for serious reactions such as myopathy including rhabdomyolysis. |
| HMG-CoA reductase inhibitors: lovastatin simvastatin |
||
| Other HMG-CoA reductase inhibitors: e.g., atorvastatin rosuvastatin |
↑ HMG-CoA reductase inhibitors | Coadministration of atazanavir and TYBOST with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with TYBOST coadministered with atazanavir or darunavir, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with atorvastatin or rosuvastatin are as follows. TYBOST coadministered with atazanavir:
TYBOST coadministered with darunavir:
|
| Other lipid-modifying agents: lomitapide |
↑ lomitapide | Coadministration with lomitapide is contraindicated due to potential for markedly increased transaminases. |
| Narcotic Analgesics For treatment of opioid dependence: buprenorphine buprenorphine/ naloxone methadone |
buprenorphine or buprenorphine/ naloxone: effects unknown methadone: effects unknown |
Initiation of buprenorphine, buprenorphine/naloxone, or methadone in patients taking TYBOST coadministered with atazanavir or darunavir: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone, or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of TYBOST coadministered with atazanavir or darunavir in patients taking buprenorphine, buprenorphine/naloxone, or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone, or methadone may be needed. Monitor clinical signs and symptoms. |
| fentanyl | ↑ fentanyl | Careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended with coadministration. |
| tramadol | ↑ tramadol | A dose decrease may be needed for tramadol with concomitant use. |
| Phosphodiesterase-5 (PDE-5) Inhibitors: avanafil sildenafil tadalafil vardenafil |
↑ PDE-5 inhibitors | Coadministration with avanafil is not recommended because a safe and effective avanafil dosage regimen has not been established. Coadministration with TYBOST coadministered with atazanavir or darunavir may result in an increase in PDE-5 inhibitor associated adverse events, including hypotension, syncope, visual disturbances, and priapism. |
Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil at a single dose not exceeding 25 mg in 48 hours, tadalafil at a single dose not exceeding 10 mg in 72 hours, or vardenafil at a single dose not exceeding 2.5 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated adverse events. |
||
| Proton-pumpInhibitors (PPIs) e.g., omeprazole |
↓ atazanavir | TYBOST coadministered with atazanavir: In treatment-naïve patients, administer TYBOST withatazanavir a minimum of 12 hours after administering PPIs. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration with PPIs, with or without tenofovir, is not recommended. |
| Sedative/ Hypnotics: midazolam (oral), triazolam |
↑ midazolam ↑ triazolam |
Coadministration with triazolam or oral administeredmidazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with TYBOST may cause large increases in the concentrations of these benzodiazepines. |
| Other benzodiazepines : e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem |
↑ sedatives/ hypnotics | Coadministration with parenteral midazolam mayincrease plasma concentrations of midazolam.Coadministration should be done in a setting thatensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosing reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. With other sedatives/hypnotics that are CYP3Ametabolized, dose reduction may be necessary and clinical monitoring is recommended. |
| a. This table is not all inclusive. b. ↑ = Increase, ↓ = Decrease, ↔ = No change |
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Included as part of the PRECAUTIONS section.
TYBOST decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating TYBOST, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance.
Prior to initiating therapy with TYBOST, assess estimated creatinine clearance [see Dosage and Administration (2.3)]. Dosage recommendations are not available for drugs that require dosage adjustments in TYBOST-treated patients with renal impairment [see Adverse Reactions (6.1), Drug Interactions (7.3), and Clinical Pharmacology (12.2)]. Consider alternative medications that do not require dosage adjustments in patients with renal impairment.
Although TYBOST may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST was used in an antiretroviral regimen that contained TDF.
In a clinical trial of TYBOST over 144 weeks (N=692), 10 (2.9%) participants treated with TYBOST coadministered with atazanavir and TRUVADA® and 11 (3.2%) participants treated with ritonavir coadministered with atazanavir and TRUVADA discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the TYBOST group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the TYBOST group had renal impairment at baseline (i.e., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of TYBOST coadministered with atazanavir and TRUVADA. Renal replacement therapy was not required in any participant.
Initiation of TYBOST, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving TYBOST, may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of TYBOST with atazanavir or darunavir.
These interactions may lead to:
These interactions may lead to:
See Table 7 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during TYBOST with atazanavir or darunavir therapy; review concomitant medications during TYBOST with atazanavir or darunavir therapy; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].
TYBOST or ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain TYBOST interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
The following antiretrovirals are not recommended in combination with TYBOST because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance:
TYBOST in combination with fixed-dose combination tablets that contain cobicistat is not recommended.
TYBOST in combination with lopinavir/ritonavir or regimens containing ritonavir is not recommended due to similar effects of TYBOST and ritonavir on CYP3A.
In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma, or rat micronucleus assays.
Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.
If overdose occurs, the patient must be monitored for evidence of toxicity. Treatment of overdose with TYBOST consists of general supportive measures including monitoring of vital signs, as well as observation of the clinical status of the patient.
As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
The concomitant use of TYBOST with atazanavir or darunavir and the following drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
*These contraindications apply only to TYBOST coadministered with atazanavir
Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir.
The effect of TYBOST on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Trial 114 in which participants with HIV-1 received atazanavir 300 mg coadministered with TYBOST 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady-state pharmacokinetic parameters of atazanavir were comparable when coadministered with TYBOST versus ritonavir groups as shown in Table 8 [see Clinical Studies (14.1)].
| Table 8 | Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in Treatment-Naïve Adults with HIV-1 (Pharmacokinetic Substudy of Trial 114) |
| Atazanavir Pharmacokinetic Parameters | TYBOST + Atazanavir + TRUVADA Once Daily | Ritonavir + Atazanavir + TRUVADA Once Daily |
| N=22 | N=26 | |
| AUCtau (mcg∙hr/mL) | 46.13 ± 26.18 | 47.59 ± 24.38 |
| Cmax (mcg/mL) | 3.91 ± 1.94 | 4.76 ± 1.94 |
| Ctau (mcg/mL) | 0.80 ± 0.72 | 0.85 ± 0.72 |
The effect of TYBOST on darunavir was evaluated in a clinical study (Trial 115) in 31 healthy participants who received darunavir 800 mg in combination with TYBOST 150 mg or ritonavir 100 mg, all once daily, for 10 days. With the exception of Ctau, the steady-state pharmacokinetic parameters of darunavir were comparable when coadministered with TYBOST versus ritonavir as shown in Table 9, and these results were similar to those reported in previous clinical trials of darunavir 800 mg with ritonavir 100 mg once daily (refer to prescribing information for darunavir).
| Table 9 | Pharmacokinetic Parameters (Mean ± SD) of Darunavir in Healthy Adults (Trial 115) |
| Darunavir Pharmacokinetic Parameters | TYBOST + Darunavir Once Daily | Ritonavir + Darunavir Once Daily |
| N=31 | N=31 | |
| AUCtau (mcg∙hr/mL) | 81.08 ± 25.15 | 79.99 ± 27.20 |
| Cmax (mcg/mL) | 7.74 ± 1.69 | 7.46 ± 1.52 |
| C0h (mcg/mL) | 2.40 ± 1.22 | 2.48 ± 0.85 |
| Ctau (mcg/mL) | 1.33 ± 0.89 | 1.87 ± 1.56 |
Cardiac Electrophysiology
In a thorough QT/QTc study in 48 healthy participants, a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in TYBOST) did not affect the QT/QTc interval. Prolongation of the PR interval was noted in participants receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for the 250 mg cobicistat dose and 20.2 (22.8) for the 400 mg cobicistat dose.
The effect of TYBOST on serum creatinine was investigated in a trial in participants with normal renal function (eGFR ≥ 80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50–79 mL/min, N=18). A statistically significant decrease in the estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFRCG) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among participants with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFRCG were observed compared to baseline for participants with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with TYBOST among participants with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFRCG, without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.1)].
In a trial where participants were instructed to take coadministered TYBOST and darunavir with food, median cobicistat peak plasma concentrations were observed approximately 3.5 hours postdose. Steady-state cobicistat Cmax, AUCtau, and Ctau (mean ± SD) values were 0.99 ± 0.3 mcg/mL (n=60), 7.6 ± 3.7 mcg∙hr/mL (n=59), and 0.03 ± 0.1 mcg/mL (n=59), respectively.
A food-effect trial was not conducted for TYBOST. In clinical trials, TYBOST was coadministered with other antiretroviral agents [see Clinical Studies (14.1)] under fed conditions, in accordance with the prescribing information for these agents. It is recommended that TYBOST coadministered with atazanavir or darunavir be administered with food [see Dosage and Administration (2.1, 2.2)].
Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
The terminal plasma half-life of cobicistat following administration of TYBOST is approximately 3 to 4 hours. With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for 6 days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively.
Race and Gender
No clinically relevant differences in the pharmacokinetics of cobicistat were observed based on race or gender.
Pediatric Patients
In pediatric participants aged 12 to less than 18 years who received TYBOST 150 mg coadministered with atazanavir 300 mg (N=12), geometric mean atazanavir Cmax and AUCtau and cobicistat AUCtau values were approximately 20-30% higher than in adults and geometric mean atazanavir and cobicistat Ctau values were approximately 60% to 160% higher than in adults; the increases were not considered clinically significant. In pediatric participants aged 12 to less than 18 years who received TYBOST 150 mg coadministered with darunavir 800 mg (N=7), geometric mean darunavir Cmax and AUCtau values were similar between adults and adolescents. Geometric mean darunavir AUCtau and Ctau values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64, 1.13) and 0.68 (90% CI: 0.30, 1.55) in adolescent participants relative to adults, respectively. This difference was not considered clinically significant based on exposure-response relationships. Geometric mean cobicistat AUCtau, Cmax, and Ctau values were comparable in adolescents and adults (Table 10).
In pediatric participants aged 6 to less than 12 years (weighing ≥ 25 kg to < 40 kg) who received TYBOST 150 mg coadministered with atazanavir (N=14) or darunavir (N=9), AUCtau and Cmax values were similar to those in adults, while the Ctrough was 33% higher for atazanavir and 44% higher for darunavir than in adults. In this study, exposures of cobicistat (AUCtau, Cmax, and Ctrough) in the combined groups were 88%, 52%, and 192%, respectively, higher than in adults (Table 10). However, the increases were not considered clinically significant.
In pediatric participants at least 2 years of age (weighing ≥ 14 kg to < 25 kg) who received TYBOST 90 mg coadministered with atazanavir (N=15) or darunavir (N=11), exposures (AUCtau, Cmax, and Ctrough) were higher for atazanavir (46%, 72% and 42%, respectively) and darunavir (49%, 88%, and 66%, respectively) as compared to exposures in adults. Exposures of cobicistat (AUCtau, Cmax, and Ctrough) in the combined groups were 58%, 29%, and 126%, respectively, higher than in adults (Table 10). However, the increases were not considered clinically significant.
| Table 10 | Multiple-Dose PK Parameters of Cobicistat, Atazanavir, and Darunavir Following Administration of TYBOST with Atazanavir or Darunavir in Pediatric Participants with HIV-1 Weighing at Least 14 kga |
| Parameter Mean (CV%) | Cobicistat | Atazanavir | Darunavir | |
| Treatment Administered | TYBOST + Atazanavir | TYBOST + Darunavir | TYBOST + Atazanavir | TYBOST + Darunavir |
| Pediatric Participants 12 to less than 18 years of age (weighing ≥ 35 kg)a,g | N=12 | N=7 | N=12 | N=7 |
| AUCtau (mcg∙hr/mL) | 12.11 (44.7) | 8.33 (34.9) | 49.48 (49.1) | 77.22 (29.5) |
| Cmax (mcg/mL) | 1.28 (31.7) | 1.10 (20.0) | 4.32 (49.9) | 7.32 (21.7) |
| Ctau (mcg/mL) | 0.09 (156.2) | 0.02 (123.9)b | 0.91 (96.4) | 0.68 (91.6) |
| Pediatric Participants 6 to less than 12 years of age (weighing ≥ 25 to < 40 kg)a,h | N=14 | N=9 | N=14 | N=9 |
| AUCtau (mcg∙hr/mL) | 21.03 (21.7)c | 13.67 (39.8) | 47.48 (38.4) | 110.51 (30.8) |
| Cmax (mcg/mL) | 2.62 (20.5) | 1.64 (29.8) | 4.19 (38.9) | 9.10 (23.9) |
| Ctau (mcg/mL) | 0.10 (118.4)c | 0.06 (109.7) | 0.92 (66.4) | 3.78 (43.2) |
| Pediatric Participants at least 2 years of age (weighing ≥ 14 kg to < 25 kg)a,h | N=15 | N=11 | N=15 | N=11 |
| AUCtau (mcg∙hr/mL) | 15.14 (39.3) | 16.07 (46.9) | 65.51 (50.8)c | 160.53 (54.0) |
| Cmax (mcg/mL) | 1.95 (37.1) | 2.08 (36.0) | 6.78 (52.0) | 15.02 (38.0) |
| Ctau (mcg/mL) | 0.06 (114.0) | 0.06 (138.6) | 0.95 (58.0)c | 2.79 (92.1) |
| Adults d,e,g | N=30d | N=21e | N=30d | N=21e |
| AUCtau (mcg∙hr/mL) | 9.65 (41.8) | 7.69 (43.9) | 39.96 (52.1) | 90.56 (45.3) |
| Cmax (mcg/mL) | 1.28 (35.6) | 1.04 (35.3) | 3.54 (45.8) | 8.34 (33.3) |
| Ctau (mcg/mL) | 0.04 (112.7) | 0.02 (135.1)f | 0.58 (84.7) | 1.00 (108.0) |
| CV=Coefficient of Variation a. From Intensive PK analysis of Trial 128. b. N=5; Data from two participants who had undetectable TYBOST Ctau concentrations were excluded from summary statistics. c. N=13 d. From pooled Intensive PK analysis of trials with TYBOST + atazanavir. e. From Intensive PK analysis of Trial GS-US-299-0102 with TYBOST + darunavir. f. N=18. g. Values are geometric means h. Values are arithmetic means |
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Patients with Renal Impairment
No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with severe renal impairment (estimated creatinine clearance below 30 mL/min) and healthy participants [see Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
No clinically relevant differences in cobicistat pharmacokinetics were observed between participants with moderate hepatic impairment (Child-Pugh Class B) and healthy participants. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7)].Pregnancy and Postpartum
The exposure to total and unbound darunavir boosted with cobicistat after intake of darunavir/cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with 6–12 weeks postpartum (see Table 11 and Figure 1).
| Table 11 | Pharmacokinetic Results of Total Darunavir after Administration of Darunavir/Cobicistat Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy, and Postpartum |
| Pharmacokinetics of total darunavir (mean ± SD) |
2nd Trimester of pregnancy N=7 |
3rd Trimester of pregnancy N=6 |
Postpartum (6−12 weeks) N=6 |
| Cmax, ng/mL | 4,340 ± 1,616 | 4,910 ± 970 | 7,918 ± 2,199 |
| AUC24h, ng.h/mL | 47,293 ± 19,058 | 47,991 ± 9,879 | 99,613 ± 34,862 |
| Cmin, ng/mL | 168 ± 149 | 184 ± 99 | 1,538 ± 1,344 |
| Figure 1 | Pharmacokinetic Results (Within-participant Comparison) of Total and Unbound Darunavir and Total Cobicistat After Administration of Darunavir/Cobicistat at 800/150 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum |
 |
Legend: 90% CI: 90% confidence interval; GMR: geometric mean ratio (i.e. second or third trimester / postpartum). Solid vertical line: ratio of 1.0; dotted vertical lines: reference lines of 0.8 and 1.25.
Drug interaction trials were conducted with TYBOST (as a single entity) and desipramine, digoxin, and efavirenz. Drug interaction trials of TYBOST coadministered with atazanavir or darunavir included atorvastatin, drospirenone/ethinyl estradiol, and rosuvastatin. Drug interaction trials of TYBOST coadministered with elvitegravir included rosuvastatin and rifabutin.
The effects of cobicistat on the exposure of coadministered drugs are shown in Table 12.
| Table 12 | Drug Interactions: Changes in Pharmacokinetic Parameter for Coadministered Drugs in the Presence of Cobicistata |
| Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information. | |
| Coadministered Drug | Dose of Coadministered Drug (mg) | TYBOST Dose (mg) | N | Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00 |
|
| Cmax | AUC | ||||
| Atorvastatin | 10 single dose | 150 once daily | 16 | 18.85b (13.53, 26.27) |
9.22b (7.58, 11.22) |
| 4.19c (3.67, 4.78) |
3.90c (3.52, 4.32) |
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| Desipramine | 50 single dose | 150 once daily | 8 | 1.24 (1.08, 1.44) |
1.65 (1.36, 2.02) |
| Digoxin | 0.5 single dose | 150 once daily | 22 | 1.41 (1.29, 1.55) |
1.08 (1.00, 1.17) |
| Drospirenone/ ethinyl estradiol | 3 drospirenone single dose | 150 once daily | 14 | 1.12b (1.05, 1.19) |
2.30b (2.00, 2.64) |
| 0.02 ethinyl estradiol single dose | 0.82b (0.76, 0.89) |
0.78b (0.73, 0.85) |
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| 3 drospirenone single dose | 150 once daily | 15 | 1.15c (1.05, 1.26) |
1.58c (1.47, 1.71) |
|
| 0.02 ethinyl estradiol single dose | 0.86c (0.77, 0.95) |
0.70c (0.63, 0.77) |
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| Efavirenz | 600 single dose | 150 once daily | 17 | 0.87 (0.80, 0.94) |
0.93 (0.89, 0.97) |
| Rosuvastatin | 10 single dose | 150 once daily | 16 | 10.58b (8.72, 12.83) |
3.42b (2.87, 4.07) |
| 3.77c (3.29, 4.32) |
1.93c (1.70, 2.20) |
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| a. All interaction studies conducted in healthy participants. b. Study conducted in the presence of 300 mg atazanavir. c. Study conducted in the presence of 800 mg darunavir. |
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Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat.
In an analysis of treatment-failure adult participants who received TYBOST coadministered with atazanavir and TRUVADA in Trial 114 through Week 144, evaluable genotypic data from paired baseline and treatment-failure isolates from participants who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in the TYBOST group (6%, 21/344). Among the 21 participants, 3 developed the emtricitabine resistance-associated substitution M184V. No participant developed the tenofovir resistance-associated substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 participants, 1 developed the emtricitabine resistance-associated substitution M184V with no tenofovir or protease inhibitor resistance-associated substitutions.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients that TYBOST coadministered with atazanavir or darunavir may interact with many drugs with potential serious implications and that some drugs are contraindicated with TYBOST coadministered with atazanavir or darunavir. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication, including acid-modifying medications or herbal products, including St. John's wort [see Contraindications (4), Warnings and Precautions (5.3), and Drug Interactions (7)].
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when TYBOST is used in combination with a TDF containing regimen [see Warnings and Precautions (5.2)].
Advise patients that TYBOST is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking TYBOST [see Use in Specific Populations (8.1)].
Inform patients that there is a pregnancy exposure registry that monitors fetal outcomes in pregnant individuals exposed to TYBOST during pregnancy [see Use in Specific Populations (8.1)].
Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission to HIV-1–negative infants, (2) developing viral resistance in HIV-1–positive infants, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].
Inform patients that TYBOST must be taken at the same time as atazanavir or darunavir and with food once daily as prescribed. It is important to take TYBOST and atazanavir or darunavir together on a regular dosing schedule and to avoid missing doses. Counsel patients about the risks of developing resistance to their HIV-1 medications.
